Opiates
An opioid is an analgesic that works by binding to opioid receptors, which are found principally in the central nervous system and the gastrointestinal tract. The receptors in these two organ systems mediate both the beneficial effects, and the undesirable side effects. There are a number of broad classes of opioids: *'natural' opiates, alkaloids contained in the resin of the opium poppy including morphine, codeine and thebaine, but not papaverine and noscapine which have a different mechanism of action; *'semi-synthetic' opiates, created from the natural opioids, such as hydromorphone, hydrocodone, oxycodone, oxymorphone, desomorphine, diacetylmorphine (Heroin), nicomorphine, dipropanoylmorphine, benzylmorphine and ethylmorphine; *'fully synthetic' opioids, such as fentanyl, pethidine, methadone, tramadol and propoxyphene; *'endogenous' opioid peptides, produced naturally in the body, such as endorphins, enkephalins, dynorphins, and endomorphins. Although the term opiate is often used as a synonym for opioid, it is more properly limited to the natural opium alkaloids and the semi-synthetics derived from them. Some minor opium alkaloids and various substances with opioid action are also found elsewhere in nature, including alkaloids present in Kratom, Corydalis, and Salvia plants and some species of poppy aside from Papaver somniferum, and there are strains which produce copious amounts of thebaine, an important raw material for making many semi-synthetic and synthetic opioids. Of all of the more than 120 poppy species, only two produce morphine. It has been discovered that the human body, as well as those of some other animals, naturally produce small amounts of morphine and codeine and possibly some of their simpler derivatives like heroin and dihydromorphine, in addition to the well known endogenous opioids. Some bacteria are capable of producing some semi-synthetic opioids such as hydromorphone and hydrocodone when living in a solution containing morphine or codeine respectively. Amongst analgesics are a small number of agents which act on the central nervous system but not on the opioid receptor system and therefore have none of the other (narcotic) qualities of opioids although they may produce euphoria by relieving pain -- a euphoria that, because of the way it is produced, does not form the basis of habituation, physical dependence, or addiction. Foremost amongst these are nefopam, orphenadrine, and perhaps phenyltoloxamine and/or some other antihistamines. The remainder of analgesics work peripherally. Research is starting to show that morphine and related drugs may indeed have peripheral effects as well, such as morphine gel working on burns, but peripherally-acting analgesics include aspirin, ibuprofen and the like. Paracetamol is predominantly a centrally acting analgesic (non-narcotic) which mediates its effect by action on descending serotonergic (5-hydroxy triptaminergic) pathways, to increase 5-HT release (which inhibits release of pain mediators). It also decreases cyclo-oxygenase activity. Many of the alkaloids and other derivatives of the opium poppy are not opioids or narcotics; the best example is the smooth-muscle relaxant papaverine. Noscapine is a marginal case as it does have CNS effects but not necessarily similar to morphine, and it is probably in a category all its own. Dextromethorphan (the stereoisomer of levomethorphan, a semi-synthetic opioid agonist) and its metabolite dextrorphan have no opioid agonist effects at all despite their structure similarity to other opioids, instead they are potent NMDA antagonists and sigma 1 and 2 agonists and are used in many over-the-counter cough suppressants. Pharmacology Opioids bind to specific opioid receptors in the central nervous system and in other tissues. There are three principal classes of opioid receptors, μ, κ, δ (mu, kappa, and delta), although up to seventeen have been reported, and include the ε, ι, λ, and ζ (Epsilon, Iota, Lambda and Zeta) receptors. Alternatively, σ (Sigma) receptors are no longer considered to be opioid receptors because: they are not reversed by the opioid inverse-agonist naloxone, they do not exhibit high-affinity binding for ketamine and phencyclidine, and they are stereoselective for dextro-rotatory isomers while the other opioid receptors are stereo-selective for laevo-rotatory isomers. In addition, there are three subtypes of μ receptor: μ1 and μ2, and the newly discovered μ3. Another receptor of clinical importance is the opioid-receptor-like receptor 1 (ORL1), which is involved in pain responses as well as having a major role in the development of tolerance to μ-opioid agonists used as analgesics. These are all G-protein coupled receptors acting on GABAergic neurotransmission. The pharmacodynamic response to an opioid depends on which receptor it binds, its affinity for that receptor, and whether the opioid is an agonist or an antagonist. For example, the supraspinal analgesic properties of the opioid agonist morphine are mediated by activation of the μ1 receptor, respiratory depression and physical dependence (dependency) by the μ2 receptor, and sedation and spinal analgesia by the κ receptor. Each group of opioid receptors elicits a distinct set of neurological responses, with the receptor subtypes (such as μ1 and μ2 for example) providing even more measurably specific responses. Unique to each opioid is their distinct binding affinity to the group(s) of opioid receptors (eg. the μ, κ, and δ opioid receptors are activated at different magnitudes according to the specific receptor binding affinities of the opioid, such as the μ opioid receptor effects being the primary receptor response to the opioid morphine, or the κ opioid receptor residing as the primary binding receptor to ketazocine). It is this primary mechanism that allows for such a wide class of opioids and molecular designs to exist, as well as their composition of slightly differing effects and side-effects, all related to their individual molecular structure/makeup (which itself is responsible for duration of action, whereby metabolic-breakdown is the primary method of opioid duration). Uses Clinical use Opioids have long been used to treat acute pain (such as post-operative pain). They have also been found to be invaluable in palliative care to alleviate the severe, chronic, disabling pain of terminal conditions such as cancer. Contrary to popular belief, high doses are not required to control the pain of advanced or end-stage disease, with the median dose in such patients being only 15 mg oral morphine every four hours (90 mg/24 hours), i.e. 50% of patients manage on lower doses, and requirements can level off for many months at a time despite the fact that opioids have some of the greatest potential for tolerance of any category of drugs. In recent years there has been an increased use of opioids in the management of non-malignant chronic pain. This practice has grown from over 30 years experience in palliative care of long-term use of strong opioids which has shown that addiction is rare when the drug is being used for pain relief. The basis for the occurrence of iatrogenic addiction to opioids in this setting being several orders of magnitude lower than the general population is the result of a combination of factors. Open and voluminous communication and meticulous documentation amongst patient, any caretakers, physicians, and chemists (pharmacists) is one part of this; the aggressive and consistent use of opioid rotation, adjuvant analgesics, potentiators, and drugs which deal with other elements of the pain (NSAIDS) and opioid side effects (stimulants in some cases, antihistamines) both improve the prognosis for the patient and appear to contribute to the rarity of addiction in these cases. The use of some opioids against depression, especially as a short-term or one-time treatment in cases of severe point-source temporary exacerbation depression or the failure of coping mechanisms in non-depressed people has been "rediscovered" in the English-speaking world in the last eight years or so although this was a common indication for some of the milder narcotic preparations prior to the Harrison Narcotic Act of 1914. A quick Google search on any day shows the following: * Drugs found to have the most marked antidepressant effects amongst those in current medical use include buprenorphine, butorphanol, oxymorphone, hydromorphone, nicomorphine, tramadol (which also works directly in the serotonin and norepinephrine systems in the body), dihydrocodeine, and piritramide. In theory, levorphanol, dromoran, ketobemidone and its relatives as well as dextromoramide should have the same general effects. * In previous centuries, laudanum and other whole-opium products were most used for this purpose. * Mixtures of tricyclic antidepressants and compatible opioids are greater than the sum of their parts for both analgesia and mood elevation and sedation. * Orphenadrine, cyclobenzaprine, cocaine, ephedrine, caffeine, scopolamine and other drugs sometimes employed as adjuncts as in the proprietary drug Trivalin, which in 1920 was a combination of the valerate salts of morphine, cocaine, and caffeine. A herbal preparation for use as a relatively mild sleep aid by this same name on the market now is in no way related to the Trivalin of decades past. Patients receiving mixtures of orphenadrine with opioids generally report that the former makes the latter "hit harder" and fill in the trough in activity as the drug wears off and eliminate some of the dysphoria associated therewith.. * Scopolamine by itself is also being tested for use as an antidepressant. * Scopolamine also has useful benzodiazepine-like effects without the potential for physical dependence &c. * The alkylamine antihistamines, especially dexclorpheniramine and chlorpheniramine work on the same principle and extended-release dexchlorpheniramine, known in most of the world as Polaramine is the most used at this time of the agents listed above for treatment of the aforementioned subset of psychological problems. United States The sole clinical indications for opioids in the United States, according to Drug Facts and Comparisons, 2005, are: * Analgesia i.e. to combat pain of various types and induction and the continuance of anesthesia as well as allaying patient apprehension right before the procedure. Fentanyl, oxymorphone, hydromorphone, and morphine are most commonly used for this purpose, in conjunction with other drugs such as scopolamine, short and intermediate-acting barbiturates, and benzodiazepines, especially midazolam which has a rapid onset of action and lasts shorter than diazepam or similar drugs. The combination of morphine (or sometimes hydromorphone) with alprazolam or midazolam or other similar benzodiazepines with or without scopolamine (rarely replaced with or used alongside Compazine, Zofran or other anti-nauseants) is colloquially called "Milk of Amnesia" amongst anesthesiologists, hospital pharmacists, physicians, radiologists, patients and others. The enhancement of the effects of each drug by the others is useful in troublesome procedures like endoscopies, complicated and difficult deliveries (pethidine and its relatives and piritramide where it is used are favoured by many practitioners with morphine and derivatives as the second line), incision & drainage of severe abcesses, intraspinal injections, and minor and moderate-impact surgical procedures in patients unable to have general anesthesia due to allergy to some of the drugs involved or other concerns. * Cough (codeine, dihydrocodeine, ethylmorphine (dionine), hydromorphone and hydrocodone, with morphine or methadone as a last resort.) * Diarrhea (generally loperamide, difenoxin or diphenoxylate, but paregoric, powdered opium or laudanum or morphine may be used in some cases of severe diarrheal diseases) * Diarrhea of Irritable Bowel Syndrome (Codeine, paregoric, diphenoxylate, difenoxin, loperamide, laudanum) * Anxiety due to shortness of breath (oxymorphone and dihydrocodeine only) * Detoxification (methadone and buprenorphine only) In the U.S., doctors virtually never prescribe opioids for psychological relief (with the narrow exception of anxiety due to shortness of breath), despite their extensively reported psychological benefits, and the widespread use of opiates in depression and anxiety up until the mid 1950s. There are virtually no exceptions to this practice, even in circumstances where researchers have reported opioids to be especially effective and where the possibility of addiction or diversion is very low—for example, in the treatment of senile dementia, geriatric depression, and psychological distress due to chemotherapy or terminal diagnosis (see Abse; Berridge; Bodkin; Callaway; Emrich; Gold; Gutstein; Mongan; Portenoy; Reynolds; Takano; Verebey; Walsh; Way). Elswhere/Investigational * Detoxification & Maintenance: dihydrocodeine, heroin, and extended-release morphine, formerly LAAM * Cough: Benzylmorphine, nicocodeine, nicodicodeine, levopropoxyphene, thebacon, acetyldihydrocodeine, methadone (1/3 the concentration of liquid for maintenance treatment of opioid dependence) Use of opioids in palliative care The current key text for palliative care is the Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle, D., Hanks, G., Cherney, I., and Calman, K., eds., Oxford University Press, 2004). This states that the indications for opioid administration in palliative care are: * "Any pain of moderate or greater severity, irrespective of the underlying pathophysiological mechanism." (p.327) * Breathlessness / shortness of breath: the largest evidence base exists for morphine. Several mechanisms are suggested for its action on breathlessness (p.605–7). * Diarrhea: codeine and loperamide are the most widely used opioid for this problem. Loperamide has the advantage of acting only on the gut, since very little is absorbed (p.493). * Painful wounds: topical morphine in an aqueous gel can be an effective agent (p.392). Their use is based on the discovery of activated opioid receptors in damaged tissue. Not just opioids… In palliative care opioids are always used in combination with adjuvant analgesics (drugs which have an indirect effect on the pain), and as an integral part of care of the whole person. Contraindications for opioids In palliative care, opioids are not recommended for sedation or anxiety because experience has found them to be ineffective agents in these roles. Some opioids are relatively contraindicated in renal failure because of the accumulation of the parent drug or their active metabolites (e.g. morphine and oxycodone). Age (young or old) is not a contraindication to strong opioids. Some synthetic opioids such as pethidine have metabolites which are actually neurotoxic and should therefore be used only in acute situations. History Non-clinical use was criminalized in the U.S by the Harrison Narcotics Tax Act of 1914, and by other laws worldwide. Since then, nearly all non-clinical use of opioids has been rated zero on the scale of approval of nearly every social institution. However, in United Kingdom the 1926 report of the Departmental Committee on Morphine and Heroin Addiction under the Chairmanship of the President of the Royal College of Physicians reasserted medical control and established the "British system" of control—which lasted until the 1960s; in the U.S. the Controlled Substances Act of 1970 markedly relaxed the harshness of the Harrison Act. Before the twentieth century, institutional approval was often higher, even in Europe and America. In some cultures, approval of opioids was significantly higher than approval of alcohol. Global shortage of poppy-based medicines Morphine and other poppy-based medicines have been identified by the World Health Organization as essential in the treatment of severe pain. However, only six countries use 77% of the world's morphine supplies, leaving many emerging countries lacking in pain relief medication.http://www.senliscouncil.net/modules/publications/008_publication. The current system of supply of raw poppy materials to make poppy-based medicines is regulated by the International Narcotics Control Board under the provision of the 1961 Single Convention on Narcotic Drugs. The amount of raw poppy materials that each country can demand annually based on these provisions must correspond to an estimate of the country's needs taken from the national consumption within the preceding two years. In many countries, underprescription of morphine is rampant because of the high prices and the lack of training in the prescription of poppy-based drugs. The World Health Organisation is now working with different countries' national administrations to train healthworkers and to develop national regulations regarding drug prescription in order to facilitate a greater prescription of poppy-based medicines.The World Health Organisation "Assuring Availability of Opioid Analgesics" www.euro.who.int/document/e76503.pdf Another idea to increase morphine availability is proposed by the Senlis Council, who suggest, through their proposal for Afghan Morphine, that Afghanistan could provide cheap pain relief solutions to emerging countries as part of a second-tier system of supply that would complement the current INCB regulated system by maintaining the balance and closed system that it establishes while providing finished product morphine to those suffering from severe pain and unable to access poppy-based drugs under the current system. Adverse effects For more information seeOxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004). and the online palliative care formulary (available on Palliativedrugs.com). Common adverse reactions in patients taking opioids for pain relief: These include: nausea and vomiting, drowsiness, itching, dry mouth, miosis, and constipation. Fortunately, most of these are not a problem (see Treating Opioid Adverse Effects below). Infrequent adverse reactions in patient taking opioids for pain relief: These include: dose-related respiratory depression (see below), confusion, hallucinations, delirium, urticaria, hypothermia, bradycardia/tachycardia, orthostatic hypotension, dizziness, headache, urinary retention, ureteric or biliary spasm, muscle rigidity, myoclonus (with high doses), and flushing (due to histamine release, except fentanyl and remifentanil). Other adverse effects: Opioid-induced hyperalgesia has been observed in some patients, whereby individuals using opioids to relieve pain may paradoxically experience more pain as a result of their medication. This phenomenon, although uncommon, is seen in some palliative care patients, most often when dose is escalated rapidly. Wilson GR, Reisfield GM. "Morphine hyperalgesia: a case report." Am J Hosp Palliat Care. 2003 Nov-Dec;20(6):459-61. PMID 14649563 Vella-Brincat J, Macleod AD. "Adverse effects of opioids on the central nervous systems of palliative care patients." J Pain Palliat Care Pharmacother. 2007;21(1):15-25. PMID 17430825 If encountered, rotation between several different opioid analgesics may mitigate the development of hyperalgesia. Mercadante S, Arcuri E. "Hyperalgesia and opioid switching." Am J Hosp Palliat Care. 2005 Jul-Aug;22(4):291-4. Review. PMID 16082916 Fine PG. "Opioid insights:opioid-induced hyperalgesia and opioid rotation." J Pain Palliat Care Pharmacother. 2004;18(3):75-9. Review. PMID 15364634 Both therapeutic and chronic use of opioids can compromise the function of the immune system. Opioids decrease the proliferation of macrophage progenitor cells and lymphocytes, and affect cell differentiation (Roy & Loh, 1996). Opioids may also inhibit leukocyte migration. However the relevance of this in the context of pain relief is not known. Treating opioid adverse effects Most adverse effects can be managed successfully. (For more complete information see Oxford Textbook of Palliative Medicine, 3rd ed. (Doyle D, Hanks G, Cherney I and Calman K, eds. Oxford University Press, 2004). and the online palliative care formulary available on Palliativedrugs.com.) Nausea: tolerance occurs within 7–10 days, during which antiemetics (e.g. low dose haloperidol 1.5–3 mg once at night) are very effective. Stronger antiemetics such as ondansetron or tropisetron may be indicated if nausea is severe or continues for an extended period, although these tend to be avoided due to their high cost unless nausea is really problematic. Vomiting: if this is due to gastric stasis (large volume vomiting, brief nausea relieved by vomiting, oesophageal reflux, epigastric fullness, early satiation) then this can be managed with a prokinetic (e.g. domperidone or metoclopramide 10 mg every eight hours), but usually needs to be started by a non-oral route (e.g. subcutaneous for metoclopramide, rectally for domperidone). Drowsiness: tolerance usually develops over 5–7 days, but if troublesome, switching to an alternative opioid often helps. Certain opioids such as diamorphine tend to be particularly sedating, while others such as oxycodone and meperidine (pethidine) tend to produce less sedation, but individual patients responses can vary markedly and some degree of trial and error may be needed to find the most suitable drug for a particular patient. Itching: tends not to be a severe problem when opioids are used for pain relief, but if required then antihistamines are useful for counteracting itching. Non-sedating antihistamines such as fexofenadine are preferable so as to avoid increasing opioid induced drowsiness, although some sedating antihistamines such as orphenadrine may be helpful as they produce a synergistic analgesic effect which allows smaller doses of opioids to be used while still producing effective analgesia. For this reason some opioid/antihistamine combination products have been marketed, such as Meprozine (meperidine/promethazine) and Diconal (dipipanone/cyclizine), which may also have the added advantage of reducing nausea as well. Constipation: this develops in 99% of patients on opioids and since tolerance to this problem does not develop, nearly all patients on opioids will need a laxative. Over 30 years experience in palliative care has shown that most opioid constipation can be successfully prevented: "Constipation … is treated laxatives and stool-softeners" (Burton 2004, 277). According to Abse, "It is very important to watch out for constipation, which can be severe” and “can be a very considerable complication” (Abse 1982, 129) if it is ignored. Peripherally acting opioid antagonists such as alvimopan and methylnaltrexone (Relistor) are currently under development which have been found to effectively relieve opioid induced constipation without affecting analgesia or triggering withdrawal symptoms.McNicol E, Boyce D, Schumann R, Carr D. Mu-opioid antagonists for opioid-induced bowel dysfunction. Cochrane Database of Systematic Reviews. 2008 Apr 16;(2):CD006332. PMID 18425947Portenoy RK, Thomas J, Moehl Boatwright ML, Tran D, Galasso FL, Stambler N, Von Gunten CF, Israel RJ. Subcutaneous methylnaltrexone for the treatment of opioid-induced constipation in patients with advanced illness: a double-blind, randomized, parallel group, dose-ranging study. Journal of Pain and Symptom Management. 2008 May;35(5):458-68. PMID 18440447 Respiratory depression: Although this is the most serious adverse reaction associated with opioid use it usually is seen with the use of a single, intravenous dose in an opioid-naive patient. In patients taking opioids regularly for pain relief, tolerance to respiratory depression occurs rapidly, so that it is not a clinical problem. Several drugs have been developed which can block respiratory depression completely even from high doses of potent opioids, without affecting analgesia, although the only respiratory stimulant currently approved for this purpose is doxapram, which has only limited efficacy in this application.Yost CS. A new look at the respiratory stimulant doxapram. CNS Drug Reviews. 2006 Fall-Winter;12(3-4):236-49. PMID 17227289Tan ZM, Liu JH, Dong T, Li JX. Clinical observation of target-controlled remifentanil infusion combined with propofol and doxapram in painless artificial abortion. (Chinese) Nan Fang Yi Ke Da Xue Xue Bao. 2006 Aug;26(8):1206-8. PMID 16939923 Newer drugs such as BIMU-8 and CX-546 may however be much more effective. Wang X, Dergacheva O, Kamendi H, Gorini C, Mendelowitz D. 5-Hydroxytryptamine 1A/7 and 4alpha receptors differentially prevent opioid-induced inhibition of brain stem cardiorespiratory function. Hypertension. 2007 Aug;50(2):368-76. PMID 17576856Ren J, Poon BY, Tang Y, Funk GD, Greer JJ. Ampakines alleviate respiratory depression in rats. American Journal of Respiratory and Critical Care Medicine. 2006 Dec 15;174(12):1384-91. PMID 16973981 Reversing the effect of opioids: Opioid effects can be rapidly reversed with an opioid antagonist (literally an inverse agonist) such as naloxone or naltrexone. These competitive antagonists bind to the opioid receptors with higher affinity than agonists but do not activate the receptors. This displaces the agonist, attenuating and/or reversing the agonist effects. However, the elimination half-life of naloxone can be shorter than that of the opioid itself, so repeat dosing or continuous infusion may be required, or a longer acting antagonist such as nalmefene may be used. In patients taking opioids regularly it is essential that the opioid is only partially reversed to avoid a severe and distressing reaction of waking in excruciating pain. This is achieved by not giving a full dose (e.g. naloxone 400 μg) but giving this in small doses (e.g. naloxone 40 μg) until the respiratory rate has improved. An infusion is then started to keep the reversal at that level, while maintaining pain relief. How safe are opioids? A world view There are a number of paradoxical beliefs about opioids: * 33% of UK doctors believe they had possibly shortened life during alleviation of symptoms, Seale C. National survey of end-of-life decisions made by UK medical practitioners, Palliative Medicine 2006; 20(1): 3–10. and yet a follow-up study showed that UK doctors are particularly cautious about shortening life. Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9. * There is a belief that the use of opioids in pain is a fine balance between relief and hastening death, and yet palliative care physicians do not find themselves faced with the dilemma of relieving symptoms at the risk of shortening life.George R, Regnard C. Lethal opioids or dangerous prescribers? Palliative Medicine, 2007; 21: 77-80. * The Dutch public equate high dose morphine and sedation with euthanasia,Rietjens JAC et al Preferences of the Dutch general public for a good death and associations with attitudes towards end-of-life decision-making. Palliative Medicine 2006; 20(7): 685–92. and yet it is the least used class of drug used for euthanasia in the Netherlands. However, studies around the globe over the past 20 years have repeatedly shown opioids to be safe when they are used correctly. In the UK two studies have shown that double doses of bedtime morphine did not increase overnight deaths,Regnard C and Badger C. Opioids, sleep and the time of death. Palliative Medicine, 1987; 1(2): 107–110. and that sedative dose increases were not associated with shortened survival (n=237).Sykes N. Thorns A. Sedative use in the last week of life and the implications for end-of-life decision making. Arch Int Med 2003: 163(3): 341–4. Another UK study showed that the respiratory rate was not changed by morphine given for breathlessness to patients with poor respiratory function (n=15).Boyd KJ. Kelly M. Oral morphine as symptomatic treatment of dyspnoea in patients with advanced cancer. Palliative Medicine. 1997: 11(4): 277–81. In Australia, no link was found between doses of opioids, benzodiazepines or haloperidol and survival.Good PD, Ravenscroft PJ, Cavenagh J. Effects of opioids and sedatives on survival in an Australian inpatient palliative care population. Int Med J. 2005: 35(9): 512–7. In Taiwan, a study showed that giving morphine to treat breathlessness on admission and in the last 48 hours did not affect survival.Hu WY, Chiu TY, Cheng SY, Chen CY. Morphine for dyspnoea control in terminal cancer patients: is it appropriate in Taiwan? J Pain & Symp Manag. 2004: 28(4): 356–63. The survival of Japanese patients on high dose opioids and sedatives in the last 48 hours was the same as those not on such drugs.Morita T, Tsunoda J, Inoue S, Chihara S. Effects of high dose opioids and sedatives on survival in terminally ill cancer patients. J Pain & Symp Manag. 2001: 21(4): 282–9. In U.S. patients whose ventilators were being withdrawn, opioids did not speed death, while benzodiazepines resulted in longer survival (n=75).Chan JD et al. Narcotic and benzodiazepines use after withdrawal of life support: association with time of death? Chest. 2004: 126(1): 286–93. Morphine given to elderly patients in Switzerland for breathlessness showed no effect on respiratory function (n=9, randomised controlled trial).Mazzocato C, Buclin T, Rapin CH. The effects of morphine on dyspnoea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind control trial. Annals of Oncology. 1999: 10(12): 1511–4. Injections of morphine given subcutaneously to Canadian patients with restrictive respiratory failure did not change their respiratory rate, respiratory effort, arterial oxygen level, or end-tidal carbon dioxide levels.Bruera E, Macmillan K, Pither J, MacDonald RN. Effects of morphine on the dyspnoea of terminal cancer patients. J Pain & Symp Manag, 1990: 5(6): 341–44. Even when opioids are given intravenously, respiratory depression is not seen.Bassam E, et al Respiratory function during parenteral opioid titration for cancer pain. Palliative Medicine, 2007; 21: 81-86. Using opioids safely * Starting doses: a person who has never been on analgesics would be started on oral morphine 2.5–5 mg every four hours (or morphine by injection 1–2.5 mg every four hours). Higher doses can be used if the patient was already on weaker analgesics. * Titration: this describes the adjustment of a drug dose to a patient, while allowing the patient’s body time to adjust to the drug to minimise adverse effects. Titration is done in 25–50% steps every 1–2 days. * Safety margin of opioids: morphine and diamorphine have a wide safety margin or "therapeutic range". * Dose range: this is very wide but usually lies between 30–500 mg per 24 hours of oral morphine, but with a median of 90 mg (or 15 mg every four hours). It is impossible to tell which patients need low doses and which need high doses, so all have to be started on low doses, unless changing from another strong opioid. Double effect The principle of double effect is not used in palliative care. Doctors are not faced with the dilemma of giving a potentially lethal drug dose to a distressed patient. A palliative care doctor gives repeated, small doses of one or more drugs, each titrated to an individual until the symptoms are eased, while doing everything possible to avoid toxicity. Doctors who give 30–60 times the required dose of morphine or diamorphine, usually as a single intravenous dose, are acting either negligently or maliciously. Since drug records should exist for opioids, there is a clear audit trail to follow if a subsequent investigation is required. With exceptions such as Shipman, UK doctors are very cautious about shortening life.Seale C. Characteristics of end-of-life decisions: survey of UK medical practitioners. Palliative Medicine 2006; 20(7): 653–9 The persistent belief that opioids and sedatives shorten life or hasten death stems from the experiences of bad practice in the use of the drugs. Evidence in the last 20 years has shown that opioids and sedatives are safe when following palliative care protocols. Clinicians who believe otherwise should be challenged to provide robust clinical evidence to support their view. Tolerance Tolerance is the process whereby neuroadaptation occurs (through receptor desensitization) resulting in reduced drug effects. Tolerance is more pronounced for some effects than for others - tolerance occurs quickly to the effects on mood, itching, urinary retention, and respiratory depression, but occurs more slowly to the analgesia and other physical side effects. However, tolerance does not develop to constipation or miosis. Tolerance to opioids is attenuated by a number of substances, including calcium channel blockersSantillán R, Maestre JM, Hurlé MA, Flórez J. "Enhancement of opiate analgesia by nimodipine in cancer patients chronically treated with morphine: a preliminary report." Pain. 1994 Jul;58(1):129-32. PMID 7970835Smith FL, Dombrowski DS, Dewey WL. "Involvement of intracellular calcium in morphine tolerance in mice." Pharmacology, Biochemistry, and Behavior. 1999 Feb;62(2):381-8. PMID 9972707, intrathecal magnesiumMcCarthy RJ, Kroin JS, Tuman KJ, Penn RD, Ivankovich AD. "Antinociceptive potentiation and attenuation of tolerance by intrathecal co-infusion of magnesium sulfate and morphine in rats." Anesthesia and Analgesia. 1998 Apr;86(4):830-6. PMID 9539610 and zincLarson AA, Kovács KJ, Spartz AK. "Intrathecal Zn2+ attenuates morphine antinociception and the development of acute tolerance." European Journal of Pharmacology. 2000 Nov 3;407(3):267-72. PMID 11068022, and NMDA antagonists such as ketamine.Wong CS, Cherng CH, Luk HN, Ho ST, Tung CS. "Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at mu-opioid receptors." Eur J Pharmacol. 1996 Feb 15;297(1-2):27-33. PMID 8851162 The cholecystokinin antagonist proglumide is also used to reduce tolerance to opioid drugs,McCleane GJ. The cholecystokinin antagonist proglumide enhances the analgesic effect of dihydrocodeine. Clinical Journal of Pain. 2003 May-Jun;19(3):200-1.Watkins LR, Kinscheck IB, Mayer DJ. Potentiation of opiate analgesia and apparent reversal of morphine tolerance by proglumide. Science. 1984 Apr 27;224(4647):395-6.Tang J, Chou J, Iadarola M, Yang HY, Costa E. Proglumide prevents and curtails acute tolerance to morphine in rats. Neuropharmacology. 1984 Jun;23(6):715-8. and newer agents such as the phosphodiesterase inhibitor ibudilast have also been researched for this application.Ledeboer A, Hutchinson MR, Watkins LR, Johnson KW. Ibudilast (AV-411). A new class therapeutic candidate for neuropathic pain and opioid withdrawal syndromes. Expert Opinion on Investigational Drugs. 2007 Jul;16(7):935-50. Magnesium and zinc deficiency speed up the development of tolerance to opioids and relative deficiency of these minerals is quite commonWHC - Magnesium Deficiency due to low magnesium/zinc content in food and use of substances which deplete them including diuretics (such as alcohol, caffeine/theophylline) and smoking. Reducing intake of these substances and taking zinc/magnesium supplements may slow the development of tolerance to opiates. Dependence Dependence is characterised by extremely unpleasant withdrawal symptoms that occur if opioid use is abruptly discontinued after tolerance has developed. The withdrawal symptoms include severe dysphoria, sweating, nausea, rhinorrea, depression, severe fatigue, vomiting and pain. Slowly reducing the intake of opioids over days and weeks will reduce or eliminate the withdrawal symptoms. The speed and severity of withdrawal depends on the half-life of the opioid — heroin and morphine withdrawal occur more quickly and are more severe than methadone withdrawal, but methadone withdrawal takes longer. The acute withdrawal phase is often followed by a protracted phase of depression and insomnia that can last for months. The symptoms of opioid withdrawal can also be treated with other medications, but with a low efficacy. Hermann D, Klages E, Welzel H, Mann K, Croissant B. Low efficacy of non-opioid drugs in opioid withdrawal symptoms. Addict Biol. 2005 Jun;10(2):165-9. PMID: 16191669 Addiction Addiction is the process whereby physical and/or psychological dependence develops to a drug - including opioids. The withdrawal symptoms can reinforce the addiction, driving the user to continue taking the drug. Psychological addiction is more common in people taking opioids recreationally, it is rare in patients taking opioids for pain relief. Several drugs have been shown to effectively block addiction to opioid drugs, most notably the plant extract ibogaineAlper KR, Lotsof HS, Kaplan CD. The ibogaine medical subculture. Journal of Ethnopharmacology. 2008 Jan 4;115(1):9-24. PMID 18029124 and its newer derivative 18-Methoxycoronaridine.Taraschenko OD, Shulan JM, Maisonneuve IM, Glick SD. 18-MC acts in the medial habenula and interpeduncular nucleus to attenuate dopamine sensitization to morphine in the nucleus accumbens. Synapse. 2007 Jul;61(7):547-60. PMID 17447255 Abuse Drug abuse is the misuse of drugs producing negative consequences. Examples of opioids Endogenous opioids Endogenous opioids are peptides that are produced in the body include: * Endorphins * Enkephalins * Dynorphins * Endomorphins β-endorphin is expressed in Pro-opiomelanocortin (POMC) cells in the arcuate nucleus and in a small population of neurons in the brainstem, and acts through μ-opioid receptors. β-endorphin has many effects, including on sexual behavior and appetite. β-endorphin is also secreted into the circulation from pituitary corticotropes and melanotropes. α-neoendorphin is also expressed in POMC cells in the arcuate nucleus. met-enkephalin is widely distributed in the CNS; met-enkephalin is a product of the proenkephalin gene, and acts through μ and δ-opioid receptors. leu-enkephalin, also a product of the proenkephalin gene, acts through δ-opioid receptors. Dynorphin acts through κ-opioid receptors, and is widely distributed in the CNS, including in the spinal cord and hypothalamus, including in particular the arcuate nucleus and in both oxytocin and vasopressin neurons in the supraoptic nucleus. Endomorphin acts through μ-opioid receptors, and is more potent than other endogenous opioids at these receptors. Opium alkaloids Phenanthrenes naturally occurring in opium: * Codeine * Morphine * Thebaine * OripavineOdell LR, Skopec J, McCluskey A. "Isolation and identification of unique marker compounds from the Tasmanian poppy Papaver somniferum N." Forensic Sci Int (2007). PMID 17765420 Preparations of mixed opium alkaloids, including papaveretum, are still occasionally used. Semisynthetic derivatives * Diacetylmorphine (heroin) * Dihydrocodeine * Hydrocodone * Hydromorphone * Nicomorphine * Oxycodone * Oxymorphone Synthetic opioids Anilidopiperidines * Fentanyl * Alphamethylfentanyl * Alfentanil * Sufentanil * Remifentanil * Carfentanyl * Ohmefentanyl Phenylpiperidines * Pethidine (meperidine) * Ketobemidone * MPPP * Allylprodine * Prodine * PEPAP Diphenylpropylamine derivatives * Propoxyphene * Dextropropoxyphene * Dextromoramide * Bezitramide * Piritramide * Methadone * Dipipanone * Levomethadyl Acetate (LAAM) * Loperamide (used for diarrhoea, does not cross the blood-brain barrier) * Diphenoxylate (used for diarrhoea, does not appreciably cross the blood-brain barrier) Benzomorphan derivatives * Dezocine * Pentazocine * Phenazocine Oripavine derivatives * Buprenorphine * Dihydroetorphine * Etorphine Morphinan derivatives * Butorphanol * Nalbuphine * Levorphanol * Levomethorphan Others * Lefetamine * Meptazinol * Tilidine * Tramadol * Tapentadol Opioid antagonists * Nalmefene * Naloxone * Naltrexone See also * Fentanyl * Psychoactive drug * Rafael Maldonado López * Opiate comparison References External links * American Pain Foundation * Pain Relief Network (PRN) * American Pain Society * American Academy of Pain Management * American Academy of Addiction Psychiatry, professional association of psychiatrists expert in addiction treatment * CLiP- Current Learning in Palliative Care Fifty-six workshops on palliative care which can be used online or downloaded. Free access, no restrictions. * International Association for Hospice and Palliative Care * Palliativedrugs.com. Online palliative care formulary. Also has bulletin board with over 22,000 international professionals registered. Free access after registration. * Palliative Care Matters Palliative Care information. * Palliative Care Handbook Online palliative care textbook * The use of opioids for chronic pain @ The APS * Merck Entry on Opioids * Pain Bibliography * Palliativedrugs.com Palliative Care Formulary and bulletin board with over 22,000 worldwide registered. Free to register. * Wall and Melzack’s textbook of pain, 5th ed. Stephen B. McMahon and Martin Koltzenburg, eds. Edinburgh : Elsevier Churchill Livingstone, 2006. * Gutstein, Howard B. and Huda Akil, “Opioid Analgesics”, in Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 11th Edition, 2006, edited by Brunton, Laurence L., John S. Lazo, Keith L. Parker, Iain L. O. Buxton, and Donald Blumenthal. * Rossi S (Ed.) (2005). Australian Medicines Handbook 2005. Adelaide: Australian Medicines Handbook. ISBN 0-9578521-9-3. * A Guide to Symptom Relief in Palliative Care, 5th ed. Regnard C, Hockley J. Abingdon: Radcliffe Medical Press, 2004 * PCF2- Palliative Care Formulary, 2nd ed. Twycross RG, Wilcock A, Charlesworth S. Abingdon: Radcliffe Medical Press, 2003. * Oxford Textbook of Palliative Medicine 3rd ed. Doyle D, Hanks G, Cherny NI, Calman K eds. Oxford : Oxford University Press, 2003. * Hanks GW. Conno F. Cherny N. Hanna M. Kalso E. McQuay HJ. Mercadante S. Meynadier J. Poulain P. Ripamonti C. Radbruch L. Casas JR. Sawe J. Twycross RG. Ventafridda V. Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. British Journal of Cancer. 2001; 84(5): 587-93. * Symptom Management in Advanced Cancer, 3rd edition. 2001. Twycross RG, Wilcock A. Abingdon: Radcliffe Medical Press. * Hanks GW. Forbes K. Opioid responsiveness. Acta Anaesthesiologica Scandinavica. 1997; 41: 154-8. * Cancer Pain Relief and Palliative Care. Geneva : WHO, 1990. * Oral Morphine, Information for Patients, Families and Friends. Twycross R., Lack S.A. Beaconsfield Publishers. 1988. Category:Opiates